The goal of this Exploratory/Developmental study is to identify DNA methylation (DNAm) profiles from across the epigenome that contribute to multiple myeloma (MM) pathogenesis. The hypothesis is that epigenomic modification in DNAm profiles is associated with altered risk of MM and among patients with MM, modifications in DNAm contribute to the excess risk observed among African Americans. To test this hypothesis, we intend to (1) compare genome-wide methylation (GWM) profiles in MM cases and controls from >450,000 CpGs in the human genome, using the Illumina Methyl450K analysis using a case-control approach stratified by European American and African American race/ethnicity, (2) compare GWM profiles in three cell types important for MM including CD138+ myeloma "tumor" cells from the bone marrow, endothelial cells from the bone marrow microenvironment and primary lymphocytes from the peripheral blood using a case-only approach and (3) compare GWM profiles between European American and African American cases of MM by cell type using a case-only approach. The extensive characterization of the MM phenotype and related risk factors from existing well-characterized populations coupled with a genome-wide approach that capitalizes on the expertise of our multidisciplinary investigative team will facilitate a rigorous and comprehensive evaluation of the effect of DNAm on MM risk that is disproportionately higher among African Americans. As the experimental relationships described in this application are characterized, we will be well-poised to facilitate biomarker discovery that can be applied to large or at-risk populations in a non-invasive and cost-effective manner. Our approach offers the best opportunity to identify novel epigenetic relationships with MM and to generate preliminary data necessary to investigate functional genomics as a tool for targeting high-risk populations who may benefit from individualized clinical management or therapeutic intervention. PUBLIC HEALTH RELEVANCE: Traditionally cancer was thought to result from genetic abnormalities such as mutations that lead to a loss of tumor suppressor genes or a gain of cancer causing genes, called oncogenes. Epigenetics is a new discipline that will help us to understand how inherited gene activity instead of genetic mutations contributes to cancer. The purpose of this study is to identify epigenetic factors that contribute to the unequal burden of multiple myeloma in African Americans. The knowledge gained from this study may help us to lower the risk of multiple myeloma and treat it more effectively.